Project Summary Allergic asthma and obesity are amongst the leading health problems in the world. Recent Meta- analysis studies implicated a positive relationship between serum leptin, an adipokine elevated in obese individuals, and the risk of asthma. However, it is not well understood how obesity- associated elevation of leptin increases the risk of asthma, representing a critical knowledge gap. This proposal will close an aspect of this gap, by exploring how leptin controls pro-allergic lymphocyte responses through targeting the endoplasmic reticulum (ER) stress-unfolded protein response (UPR) pathway and contributes to allergic reactions. Fully understanding the role of leptin in control of allergic inflammation may suggest novel methods for treatment of allergic airway disease. Our immediate objective is to determine how leptin regulates the development and function of pro-allergic lymphocytes and controls allergic inflammation. Given the UPR pathway play an essential role in secretory cell function (Scientific Premise), we formulate a novel hypothesis that leptin may activate the UPR pathway that promotes pro-allergic lymphocyte responses and exacerbates allergic airway inflammation. Specific Aims: Aim 1. Determine the role of leptin-XBP1 axis in allergic lymphocyte responses; Aim 2. Delineate the molecular mechanism whereby leptin induces the expression of ER stress-UPR factors and confirm the UPR-dependent function of leptin in allergic reactions in vivo. This project is significant since it will bridge obesity and the development of allergic asthma by the pathogenic role of leptin-mediated ER-stress-UPR. This project might lead to new options for the development of therapeutic approaches. The proposed research is innovative because we will investigate a previously unknown regulatory pathway in pro-allergic lymphocytes, by which leptin promotes allergic reactions.